Despite an explosion in preclinical research of pain mechanisms and pharmacology, little is known about the utility of non-opioid analgesics in humans or the predictability of animal models of pain or experimental pain in volunteers to the pharmacology of pain treatment in the clinic. This grant performs two functions: to investigate intrathecal injection of novel non-opioid compound for analgesia in humans and to perform neurotoxicity screening to support clinical trials in subsequent cycles. Since 1992, we have introduced clonidine, neostigmine, and adenosine into clinical trails and probed their mechanisms of action and efficacy in animals, volunteers with experimentally induced pain, and patients. In the last cycle we have completed preclinical safety studies of the cyclooxygenase (COX) inhibitor, ketorolac, and are nearly completed with a Phase I safety trial. Preliminary data in rats demonstrate efficacy of intrathecal ketorolac in postoperative pain, and a large upregulation of COX-1 in the spinal cord after surgery. Thus, our first 2 specific aims are: 1. Determine in humans the efficacy of i.t. Ketorolac to treat inflammatory and postoperative pain, and determine ketorolac's CSF pharmacokinetics and dynamics 2. Determine in rats the role of cyclooxygenase isoenzymes and their alteration by AMPA receptor and glial activation in surgery-induced hypersensitivity and its blockade by ketorolac In addition, we have selected as our next target for animal and human testing the clonidine analog, ST9 1. This compound, described over 25 years ago, produces minimal or no hypotension or sedation after intrathecal injection and likely acts at an alpha2-nonA adrenoceptor subtype, which we believe represents the key target for a2 agonists to treat neuropathic pain. Thus, our last specific aim is: 3. Synthesize and perform neurotoxicity testing for ST91 to support IND application These studies will continue the remarkable success of this program to generate novel hypotheses regarding pharmacologic mechanisms and guide preclinical and clinical development in pain treatment.